The FDA’s Oncologic Drugs Advisory Committee (ODAC) has voted 10 to 3 that the overall risk–benefit profile of oral L-glutamine powder (Endari, Emmaus Life Sciences) for the treatment of patients with sickle cell disease (SCD) is favorable. The FDA has set a PDUFA target action date of July 7, 2017.
The FDA is not bound by its advisory panels’ recommendations but takes their advice into consideration when reviewing new drug applications (NDAs). If approved, Endari would be the first FDA-cleared treatment for pediatric patients with SCD, and the first new treatment in almost 20 years for adults.
In September 2016, Emmaus Medical submitted an NDA for Endari, seeking approval for the proposed indication of the treatment of patients with SCD. The drug is intended for chronic use in adult and pediatric patients 5 years of age and older with SCD. The application was granted a standard 10-month review.
The submission included data from a phase 3 randomized, open-label, double-blind, placebo-controlled study involving 230 patients 5 years of age or older with SCD or sickle ß0-thalassemia. Subjects with at least two episodes of painful crises during the 12 months prior to screening were randomly assigned to receive oral L-glutamine 0.3 mg/kg a day or placebo for 48 weeks, followed by a three-week tapering period and a two- week follow-up period, for a total duration of up to 57 weeks.
The primary efficacy endpoint was the number of sickle cell crises through week 48 and before the start of taper, with a sickle cell crisis defined as a visit to an emergency room or medical facility for SCD-related pain that was treated with a parenterally administered narcotic or parenterally administered ketorolac.
The mean number of sickle cell crises at 48 weeks was 3.2 for L-glutamine compared with 3.9 for placebo (P = 0.005). However, while the primary efficacy analysis was statistically significant in favor of treatment with L-glutamine, issues with data imputation and analysis overshadowed this finding, according to an FDA briefing document.
Moreover, the discontinuation rate in this study was higher than anticipated (32% compared with the expected 25%), and there was a disparate rate of premature discontinuations between treatment arms (36% in the L-glutamine group vs. 24% in the placebo group). According to the briefing document, the data collected during the study were insufficiently detailed to allow reviewers to determine the reason(s) for the higher withdrawal rate in the L-glutamine arm.